Background-Atherosclerosis is an inflammatory disease in which interferon (IFN)-␥, the signature cytokine of Th1 cells, plays a central role. We investigated whether interleukin (IL)-17, the signature cytokine of Th17 cells, is also associated with human coronary atherosclerosis. Methods and Results-Circulating IL-17 and IFN-␥ were detected in a subset of patients with coronary atherosclerosis and in referent outpatients of similar age without cardiac disease but not in young healthy individuals. IL-17 plasma levels correlated closely with those of the IL-12/IFN-␥/CXCL10 cytokine axis but not with known Th17 inducers such as IL-1␤, IL-6, and IL-23. Both IL-17 and IFN-␥ were produced at higher levels by T cells within cultured atherosclerotic coronary arteries after polyclonal activation than within nondiseased vessels. Combinations of proinflammatory cytokines induced IFN-␥ but not IL-17 secretion. Blockade of IFN-␥ signaling increased IL-17 synthesis, whereas neutralization of IL-17 responses decreased IFN-␥ synthesis; production of both cytokines was inhibited by transforming growth factor-␤1. Approximately 10-fold fewer coronary artery-infiltrating T helper cells were IL-17 producers than IFN-␥ producers, and unexpectedly, IL-17/IFN-␥ double producers were readily detectable within the artery wall. Although IL-17 did not modulate the growth or survival of cultured vascular smooth muscle cells, IL-17 interacted cooperatively with IFN-␥ to enhance IL-6, CXCL8, and CXCL10 secretion. Conclusions-Our findings demonstrate that IL-17 is produced concomitantly with IFN-␥ by coronary arteryinfiltrating T cells and that these cytokines act synergistically to induce proinflammatory responses in vascular smooth muscle cells.

Ischemia-reperfusion (I/R) injury is a process whereby an initial hypoxic insult and subsequent return of blood flow leads to the propagation of innate immune responses and organ injury. The necessity of the pattern recognition receptor, toll-like receptor (TLR)-4, for this innate immune response has been previously shown. However, TLR4 is present on various cell types of the liver, both immune and non-immune cells. Therefore, we sought to determine the role of TLR4 in individual cell populations, specifically parenchymal hepatocytes, myeloid cells including Kupffer cells, and dendritic cells following hepatic I/R. When hepatocyte specific (Alb-TLR4-/-) and myeloid cell specific (Lyz-TLR4-/-) TLR4 knockout mice were subjected to warm hepatic ischemia there was significant protection in these mice compared to wild-type (WT). However, the protection afforded in these two strains was significantly less than global TLR4 specific TLR4 knockout (TLR4-/-) mice. Dendritic cell specific TLR4-/- (CD11c-TLR4-/-) mice had significantly increased hepatocellular damage compared to WT mice. Circulating levels of high mobility group box-1 (HMGB1) were significantly reduced in the Alb-TLR4-/- mice compared to WT, Lyz-TLR4-/-, CD11c-TLR4-/- mice and equivalent to global TLR4-/- mice, suggesting that TLR4 mediated HMGB1 release from hepatocytes may be a source of HMGB1 after I/R. Hepatocytes exposed to hypoxia responded by rapidly phosphorylating the mitogen-activated protein kinases JNK and p38 in a TLR4-dependent manner; inhibition of JNK decreased the release of HMGB1 after both hypoxia in vitro and I/R in vivo. Conclusion These results provide insight into the individual cellular response of TLR4. It was found that the parenchymal hepatocyte is an active participant in the sterile inflammatory response after I/R through TLR4-mediated activation of pro-inflammatory signaling and release of danger signals such as HMGB1.

Interleukin (IL) 1 ␣ produced by human endothelial cells (ECs), in response to tumor necrosis factor (TNF) or to co-culture with allogeneic T cells in a TNF-dependent manner, can augment the release of cytokines from alloreactive memory T cells in vitro. In a humanmouse chimeric model of artery allograft rejection, ECs lining the transplanted human arteries express IL-1 ␣ , and blocking IL-1 reduces the extent of human T cell infi ltration into the artery intima and selectively inhibits IL-17 production by infi ltrating T cells. In human skin grafts implanted on immunodefi cient mice, administration of IL-17 is suffi cient to induce mild infl ammation. In cultured cells, IL-17 acts preferentially on vascular smooth muscle cells rather than ECs to enhance production of proinfl ammatory mediators, including IL-6, CXCL8, and CCL20. Neutralization of IL-17 does not reduce T cell infi ltration into allogeneic human artery grafts, but markedly reduces IL-6, CXCL8, and CCL20 expression and selectively inhibits CCR6 + T cell accumulation in rejecting arteries. We conclude that graft-derived IL-1 can promote T cell intimal recruitment and IL-17 production during human artery allograft rejection, and suggest that targeting IL-1 in the perioperative transplant period may modulate host alloreactivity.

Dendritic cells (DCs) are potent antigen-presenting cells critical in regulating the adaptive immune response. The role of DCs is dichotomous; they may both present antigens and the appropriate stimulatory molecules to initiate an adaptive immune response, or they may induce tolerance and release anti-inflammatory signals. The activation of immature DCs, required for the expression of the necessary costimulatory T cell molecules, is dependent on pattern recognition receptors. In addition to the pathogen-derived ligands of pattern recognition receptors, several damage-associated molecular patterns (DAMPs) have recently been shown to interact with DCs and dramatically affect their ultimate function. The complex interplay of DAMPs on DCs is clinically important, with implications for transplantation, tumor immunity, autoimmunity, chronic inflammation and other conditions of sterile inflammation such as ischemia reperfusion injury. In this review, we will focus on the role of DAMPs in DC function.

Atherosclerosis and graft arteriosclerosis are characterized by leukocytic infiltration of the vessel wall that spares the media. The mechanism(s) for medial immunoprivilege is unknown. In a chimeric humanized mouse model of allograft rejection, medial immunoprivilege was associated with expression of IDO by vascular smooth muscle cells (VSMCs) of rejecting human coronary artery grafts. Inhibition of IDO by 1-methyl-tryptophan (1-MT) increased medial infiltration by allogeneic T cells and increased VSMC loss. IFN-γ-induced IDO expression and activity in cultured human VSMCs was considerably greater than in endothelial cells (ECs) or T cells. IFN-γ-treated VSMCs, but not untreated VSMCs nor ECs with or without IFN-γ pretreatment, inhibited memory Th cell alloresponses across a semipermeable membrane in vitro. This effect was reversed by 1-MT treatment or tryptophan supplementation and replicated by the absence of tryptophan, but not by addition of tryptophan metabolites. However, IFN-γ-treated VSMCs did not activate allogeneic memory Th cells, even after addition of 1-MT or tryptophan. Our work extends the concept of medial immunoprivilege to include immune regulation, establishes the compartmentalization of immune responses within the vessel wall due to distinct microenvironments, and demonstrates a duality of stimulatory EC signals versus inhibitory VSMC signals to artery-infiltrating T cells that may contribute to the chronicity of arteriosclerotic diseases.

rVAAs have significant mortality. Open and endovascular interventions are equally durable for elective repair of VAAs, but endovascular interventions for rVAAs result in lower morbidity and mortality. Aggressive treatment of pseudoaneurysms is electively recommended at diagnosis regardless of size.

Inflammation is associated with the pathogenesis of coronary atherosclerosis, although the mechanisms remain unclear. We investigated whether cytokine secretion by innate immune responses could contribute to the production of proarteriosclerotic Th1-type cytokines in human coronary atherosclerosis. Cytokines were measured by ELISA in the plasma of patients with coronary atherosclerosis undergoing cardiac catheterization. IL-18 was detected in all subjects, whereas a subset of patients demonstrated a coordinated induction of other IFN-γ-related cytokines. Specifically, elevated plasma levels of IL-12 correlated with that of IFN-γ and IFN-γ-inducible chemokines, defining an IFN-γ axis that was activated independently of IL-6 or C-reactive protein. Systemic inflammation triggered by cardiopulmonary bypass increased plasma levels of the IFN-γ axis, but not that of IL-18. Activation of the IFN-γ axis was not associated with acute coronary syndromes, but portended increased morbidity and mortality after 1-year follow-up. IL-12 and IL-18, but not other monokines, elicited secretion of IFN-γ and IFN-γ-inducible chemokines in human atherosclerotic coronary arteries maintained in organ culture. T cells were the principal source of IFN-γ in response to IL-12/IL-18 within the arterial wall. This inflammatory response did not require, but was synergistic with and primed for TCR signals. IL-12/IL-18-stimulated T cells displayed a cytokine-producing, nonproliferating, and noncytolytic phenotype, consistent with previous descriptions of lymphocytes in stable plaques. In contrast to cognate stimuli, IL-12/IL-18-dependent IFN-γ secretion was prevented by a p38 MAPK inhibitor and not by cyclosporine. In conclusion, circulating IL-12 may provide a mechanistic link between inflammation and Th1-type cytokine production in coronary atherosclerosis.

Most OCs after EVAR are associated with significant morbidity and mortality, except when electively treating an isolated type II endoleak with ligation of branches and preservation of the endograft.